embryonic stem
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2022 ◽  
Vol 146 ◽  
pp. 112589
Author(s):  
Julius Niehoff ◽  
Matthias Matzkies ◽  
Filomain Nguemo ◽  
Jürgen Hescheler ◽  
Michael Reppel

2022 ◽  
Author(s):  
Ninel Miriam Vainshelbaum ◽  
Kristine Salmina ◽  
Bogdan I Gerashchenko ◽  
Marija Lazovska ◽  
Pawel Zayakin ◽  
...  

The Circadian Clock (CC) drives the normal cell cycle and reciprocally regulates telomere elongation. However, it can be deregulated in cancer, embryonic stem cells (ESC) and the early embryo. Here, its role in the resistance of cancer cells to genotoxic treatments was assessed in relation to whole-genome duplication (WGD) and telomere regulation. We first evaluated the DNA damage response of polyploid cancer cells and observed a similar impact on the cell cycle to that seen in ESC - overcoming G1/S, adapting DNA damage checkpoints, tolerating DNA damage, and coupling telomere erosion to accelerated cell senescence, favouring transition by mitotic slippage into the ploidy cycle (reversible polyploidy). Next, we revealed a positive correlation between cancer WGD and deregulation of CC assessed by bioinformatics on 11 primary cancer datasets (rho=0.83; p<0.01). As previously shown, the cancer cells undergoing mitotic slippage cast off telomere fragments with TERT, restore the telomeres by recombination and return their depolyploidised mitotic offspring to TERT-dependent telomere regulation. Through depolyploidisation and the CC "death loop", the telomeres and Hayflick limit count are thus again renewed. This mechanism along with similar inactivity of the CC in early embryos supports a life-cycle (embryonic) concept of cancer.


2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Bret Sanders ◽  
Daniel D’Andrea ◽  
Mark O. Collins ◽  
Elliott Rees ◽  
Tom G. J. Steward ◽  
...  

AbstractCoordinated programs of gene expression drive brain development. It is unclear which transcriptional programs, in which cell-types, are affected in neuropsychiatric disorders such as schizophrenia. Here we integrate human genetics with transcriptomic data from differentiation of human embryonic stem cells into cortical excitatory neurons. We identify transcriptional programs expressed during early neurogenesis in vitro and in human foetal cortex that are down-regulated in DLG2−/− lines. Down-regulation impacted neuronal differentiation and maturation, impairing migration, morphology and action potential generation. Genetic variation in these programs is associated with neuropsychiatric disorders and cognitive function, with associated variants predominantly concentrated in loss-of-function intolerant genes. Neurogenic programs also overlap schizophrenia GWAS enrichment previously identified in mature excitatory neurons, suggesting that pathways active during prenatal cortical development may also be associated with mature neuronal dysfunction. Our data from human embryonic stem cells, when combined with analysis of available foetal cortical gene expression data, de novo rare variants and GWAS statistics for neuropsychiatric disorders and cognition, reveal a convergence on transcriptional programs regulating excitatory cortical neurogenesis.


2022 ◽  
Vol 23 (2) ◽  
pp. 893
Author(s):  
María José Peña-Gómez ◽  
Marina Suárez-Pizarro ◽  
Iván V. Rosado

Whilst avoidance of chemical modifications of DNA bases is essential to maintain genome stability, during evolution eukaryotic cells have evolved a chemically reversible modification of the cytosine base. These dynamic methylation and demethylation reactions on carbon-5 of cytosine regulate several cellular and developmental processes such as embryonic stem cell pluripotency, cell identity, differentiation or tumourgenesis. Whereas these physiological processes are well characterized, very little is known about the toxicity of these cytosine analogues when they incorporate during replication. Here, we report a role of the base excision repair factor XRCC1 in protecting replication fork upon incorporation of 5-hydroxymethyl-2′-deoxycytosine (5hmC) and its deamination product 5-hydroxymethyl-2′-deoxyuridine (5hmU) during DNA synthesis. In the absence of XRCC1, 5hmC exposure leads to increased genomic instability, replication fork impairment and cell lethality. Moreover, the 5hmC deamination product 5hmU recapitulated the genomic instability phenotypes observed by 5hmC exposure, suggesting that 5hmU accounts for the observed by 5hmC exposure. Remarkably, 5hmC-dependent genomic instability and replication fork impairment seen in Xrcc1−/− cells were exacerbated by the trapping of Parp1 on chromatin, indicating that XRCC1 maintains replication fork stability during processing of 5hmC and 5hmU by the base excision repair pathway. Our findings uncover natural epigenetic DNA bases 5hmC and 5hmU as genotoxic nucleosides that threaten replication dynamics and genome integrity in the absence of XRCC1.


2022 ◽  
Author(s):  
Michael A Schon ◽  
Stefan Lutzmayer ◽  
Falko Hofmann ◽  
Michael D Nodine

Accurate annotation of transcript isoforms is crucial for functional genomics research, but automated methods for reconstructing full-length transcripts from RNA sequencing (RNA-seq) data are imprecise. We developed a generalized transcript assembly framework called Bookend that incorporates data from multiple modes of RNA-seq, with a focus on identifying, labeling, and deconvoluting RNA 5′ and 3′ ends. Through end-guided assembly with Bookend we demonstrate that correctly modeling transcript start and end sites is essential for precise transcript assembly. Furthermore, we discover that reads from full-length single-cell RNA-seq (scRNA-seq) methods are sparsely end-labeled, and that these ends are sufficient to dramatically improve precision of assembly in single cells. Finally, we show that hybrid assembly across short-read, long-read, and end-capture RNA-seq in the model plant Arabidopsis and meta-assembly of single mouse embryonic stem cells (mESCs) are both capable of producing tissue-specific end-to-end transcript annotations of comparable or superior quality to existing reference isoforms.


Biology Open ◽  
2022 ◽  
Vol 11 (1) ◽  
Author(s):  
Silvie Franck ◽  
Edouard Couvreu De Deckersberg ◽  
Jodi L. Bubenik ◽  
Christina Markouli ◽  
Lise Barbé ◽  
...  

ABSTRACT Skeletal muscle tissue is severely affected in myotonic dystrophy type 1 (DM1) patients, characterised by muscle weakness, myotonia and muscle immaturity in the most severe congenital form of the disease. Previously, it was not known at what stage during myogenesis the DM1 phenotype appears. In this study we differentiated healthy and DM1 human embryonic stem cells to myoblasts and myotubes and compared their differentiation potential using a comprehensive multi-omics approach. We found myogenesis in DM1 cells to be abnormal with altered myotube generation compared to healthy cells. We did not find differentially expressed genes between DM1 and non-DM1 cell lines within the same developmental stage. However, during differentiation we observed an aberrant inflammatory response and increased CpG methylation upstream of the CTG repeat at the myoblast level and RNA mis-splicing at the myotube stage. We show that early myogenesis modelled in hESC reiterates the early developmental manifestation of DM1.


2022 ◽  
Author(s):  
Alessandro Dasti ◽  
Maria Carla Antonelli ◽  
Magdalena Arnal Segura ◽  
Alexandros Armaos ◽  
Sarah Bonnin ◽  
...  

The signal transduction and activation of RNA (STAR) family is composed of RNA-binding proteins (RBPs) that play a central role in mammalian development. Nonetheless, the functions and modes of action that STAR proteins have in lineage specification are still poorly understood. Here, we characterized the role of STAR proteins SAM68 and QUAKING (QKI) in pluripotency and differentiation by performing their depletion through CRISPR-Cas9 in mouse embryonic stem cells (mESCs). Combining RNA-sequencing, ribosome profiling and advanced computational predictions, we found that both SAM68 and QKI regulate the mESCs self-renewal and are indispensable for cardiomyocyte differentiation. At the molecular level, we discovered that SAM68 and QKI antagonistically control the expression of cardiogenic factors. Our calculations indicated that SAM68, unlike QKI, binds the cardiogenic-specific transcription factor Gata4 in a region spanning nucleotides 500 to 1000 of the mRNA corresponding to part of the 5' untranslated region and the first exon. We validated the predictions by electrophoretic mobility shift assay and RNA immunoprecipitation showing that SAM68 controls the translation of Gata4 during mESCs differentiation towards the cardiomyocyte lineage.


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